Preparation of 2-mercaptoimidazole



though tests 'made r also active as anti thyroid agents.

Patented Aug. 15, 1950 2,519,310 l PREPARAT IUN-OF Z-MERGAPT'O IM ID AZOLE :Alic M. Dessert-,' Old Greenwich, Conmg'as'signor to -An'ieri'cari CyanamidxCompanw New York, n'N':-'Y.'; a corporation of Maine "No'DraWing, Application December 1, 1948, "Serial No. 62,980

'2 Claims.

-ing.-.alkyl substituents vin ithe. imidaaole .ring are T It appears -likely, .therefore, .thatthere will be. a demand for considerable quantities of these. compounds .foruse in medicine.

-- mercaptoimidazoles are obtained. 1 the potential l l demand for 1 large quantities of flUnfortunately presently J.known methods. of, preparing thel' 2-mercapto-' imid'azoles are not satisfactory.

' Marckwald described the s'production of l '2- mercaptoimidazole as early as 1892 in" Berichte,

volume 25, page 2354. *He'used as starting materials aminoacetal'-' and potassium thiocyanate in an involved process requiring many steps. The product of the reaction is difficult to handle,

and extremely low *yields of the desired 2- 2-rnercaptoimidazole l and alkyl rnercaptoimid- 'azoles -it isdesirable; thereiore, that a method 1 of rproducing these substances on a commercial scale be made available. Ihe present invention describes such-a. method, which uses readily 30 available materialsand .g1ves, under-fav0rable -conditions; almost quantitative yields.

. In brief the new. process of the. present -invention involves the cleavage of ai thioether with l an alkali metalas -illustrated by the. followingffm equation:

-.radicaland: R: an" alkyl' or' aralkyl radical. 1i resuIting' prdduct, anialkali nietal saltfbf the fi Ii mercaritoimidazole; -is readily converted to the The ' de'sired free "-mercaptoimidazol' by neutralization with an acid or by treatment-*vvitha'salt diverse agents" as P235, dry hydrogem chloride,

"sodium metal in ethah'oL" acetic acid," and-hydrogen iodide? and still other agentswhich" have "been usedebefore to cleave thioethers wereun- 5 able tocleavlth 2-mereaptoimidazolethioethers --whiclr are usedherein as intermediates.

It is preferred that the reaction be conducted in liquid ammonia which serves as a solvent and tends to reduce the hazards of the reaction.

\ The "temperature of the reaction is not"'ci-itical,

-'"but care'should be" taken to keep thereaction mixture-in liquid 'form'to reduce the" d'ahg'eriof an explosion ifrom the sod-amide; which maybe formed under these 'c'Ohditi'bnsfiby the addition,

Ordinarilyy "der'these'conditions the reactiontakes placc at low "temperatures," but in" pressure vessels it possible to keep 'the"'ammonia' in liquid form at higher temperatures. Sodium is the preferred alkali metal because of its cheapness, -but other alkali-"metals' 'slichas potassiumor if lithium mayhe used. Theoretically," the" "reaction requires"at least two mhles'of the alkali metal for*"each"1n'ole- 0f"=the f mercaptoimidazoleti iio tl'ierfbutit"is preferld th'at three 170 seven mores-or the 'allialinfetal be used. c

The reaction takes place "within a" very short time" and "is-generally" considered to becO'mp'1ete *whenthe blue" color "of *the" alkali metal in" the -li'quid arhmenia'-disappears. W'ater is then added -'to"- decompose the alkali metal amide," and "the ammonia and-waterremoved by evaporation. The product contains*the alkali-metalsaltbf the Z-mercaptoimidazole. 7 On neutralization with an acid or ammonium chloride or the like the fre m'ercaptoimidaaole"is obtained mcxcel- 1 1 nt yie1ds. Thec'rude '-'product may be pari- -fied by recrystallization from solvents.

Examples showing 3 the preparation of '2- 2 40 "mercaptoi'mldazole and alkylsubstituted mercaptoimidazoles from representative Z-tlkyl and 2 arallylthioimidazoles"willnow beEiven. *It "#Will be"understood; of --coursethat' other 2 a1ky1 ana z-aralkylthicimidazcles may be used and at the process is=not limi-ted to -the "exactconditions described.

lExamplc l To" 1 1 :40: g, 0.94 resale) of rlfethyl 'iso'thi'ourea e distill-ed.ibromacetaldehyde; and th' mirture was stirredron t /z hou rs on a steam bath at' 85?7C. The; solution was made basic with r otassium carbonate s sblution and tifen th'er 'ei-tracted. For example; such;jfb5-.. Concerrtrationcof the' ethcr asolution," gave 2- Mixed melting point by another process was Example 2 To a solution of 4.4 g. (0.034 mole) of 2-ethylthioimidazole in liquid ammonia were added 2.5 g. (0.102 mole) of sodium. In 40 minutes the blue color disappeared, and water was added to the solution. The ammonia and water were removed at low pressure, and the residue was neutralized with dilute HCl. An acetone extraction of the solid obtained gave 3.3 g. 97% yield) of Z-mercaptoimidazole melting at about 226 0.

Example 3 To g. (0.026 mole) of 2-benzylthioimidazole dissolved in liquid ammonia were added 1.79 g. (0.078 mole) of sodium. The blue solution was stirred for about one hour and then water was added. The ammonia and water were removed using reduced pressure, and the residue was neutralized with dilute HCl. Recrystallization of 2.8 g. of crude material from water gave 1 g. (38% yield) of pure Z-mercaptoimidazole,

Example 4 Two grams of 2-methylthio-4(5)-n propylimidazole was dissolved in liquid ammonia and .88 g. (0.0384 gram atom) sodium was added. After stirring for one hour, some blue color remained. About 5 cc. of alcohol were added and then the excess ammonia and the alcohol were removed. To the residue was added about cc. of water and then the solution was neutralized with HCl. Two grams of crude material separated. This was recrystallized once from Water using activated charcoal. One gram of 4(5) n-propyl-Z-mercaptoimidazole melting at 182-183 C. was obtained, filtered and dried.

Example 5 Five grams of 1-methyl-2-mercaptoimidazole was dissolved as much as possible in chloroform and grams of methyl iodide was added. The solution was refluxed for two hours and then cooled. A small amount of solid was filtered. The solution was concentrated and the residue treated with ether. Five grams of solid were obtained, melting at around 145 C. The hydroiodide salt of the desired compound is reported to melt at 148 C. (Marckwald, Ber. 22, 1356). The solid was dissolved in water and treated with potassium carbonate. It was finally found that the free base was not obtained in any quantity until the pH was brought up to 11 with potassium hydroxide solution. At this pH a sharp mercaptan-like odor was noticed. The solution was concentrated and the residue was treated with ether. The ether solution was dried briefly over potassium hydroxide and then was concentrated. This oily residue was dried in a desiccator. One gram 0.

1-methyl-2-methylthioimidazole, possibly still wet, was obtained.

The gram of oily material obtained above was dissolved in liquid ammonia and 0.53 g. (0.0231 gram atom) of sodium was added. After onehalf hour the blue color had disappeared, and 5 cc. of alcohol were added. Then the excess ammonia and alcohol were removed. To the residue were added 10 cc. of water. This solution was neutralized with hydrochloric acid and then concentrated to dryness. The residue was treated with alcohol, filtered and the alcohol concentrated. The product, l-methyl-Z-mercaptoimidazole was recrystallized from water.

This is a continuation-in-part of my application, Serial No. 5,200, filed January 29, 1948, now abandoned.

I claim:

1. The process of preparing alkali metal salts of Z-mercaptoimidazoles which comprises the step of treating a 2-mercaptoimidazolethioether having the general formula of treating a 2-mercaptoimidazolethioether having the general formula in which R is a radical of the group consisting of hydrogen and alkyl radicals and R is a member of the group consisting of alkyl and aralkyl radicals, with metallic sodium in liquid ammonia whereby the thioether is cleaved and a sodium Z-mercaptoimidazole is obtained.

3. A method of preparing sodium Z-mercaptoimidazole which comprises treating a 2-alkylmercaptoimidazole with sodium in liquid ammonia whereby sodium 2-mercaptoimidazole is formed.

4. A method of preparing sodium 2-mercaptoimidazole which comprises treating Z-methylmercaptoimidazole with sodium in liquid ammonia whereby sodium Z-mercaptoimidazole is formed.

5. A method of preparing sodium 4(5)-n propyl-2-mercaptoimidazole which comprises treating 2-methylthio-4(5)-n propylimidazole with sodium in liquid ammonia whereby sodium 4(5) n propyl-2-mercaptoimidazole is formed.

6. A method of preparing sodium l-methyl- Z-mercaptoimidazole which comprises treating 1-methyl-2-methylthioimidazole with sodium in liquid ammonia whereby sodium 1-methyl-2- mercaptoimidazole is formed.

7. A method of preparing 2-mercaptoimidazoles having the general formula which comnrises treating a compound having the formula.

R I3: I3 R N N-R in in which R is a member of the group consisting of hydrogen and alkyl radicals and R is a memher of the group consisting of alkyl and aralkyl radicals with an alkali metal in liquid ammonia and after reaction thereof whereby the thioether linkage is cleaved, neutralizing the reaction product with an acid to obtain 2-mercaptoimidazoles having the first illustrated formula above.

ALICE M. DESSERT.

No references cited. 

7. A METHOD OF PREPARING 2-MERCAPTIOMIDAZOLES HAVING THE GENERAL FORMULA 